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BMJ Open Dec 2021Phase I/II clinical trials suggested that the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathway-targeted agents were active in suppression...
Comparative efficacy and safety of anti-HGF/MET pathway agents plus chemotherapy versus chemotherapy alone as first-line treatment in advanced gastric cancer: a protocol for a systematic review and meta-analysis.
INTRODUCTION
Phase I/II clinical trials suggested that the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathway-targeted agents were active in suppression of gastric cancer (GC). Randomised controlled trials (RCTs) were undertaken assessing whether the addition of anti-HGF/MET agent (rilotumumab or onartuzumab) to chemotherapy improves survival outcomes of advanced GC, but conflict conclusions were reached. Therefore, we plan to perform this systematic review and meta-analysis to synthesise evidence concerning efficacy and safety of anti-HGF/MET agents combined with chemotherapy as the first-line treatment to advanced GC.
METHODS AND ANALYSIS
Systematic searches of the PubMed, Embase and the Cochrane Central Register of Controlled Trials will be performed with no language restriction from inception to 31 January 2022 to identify RCTs exploring the comparative efficacy and safety of anti-HGF/MET agents plus chemotherapy as first-line treatment in advanced GC. The primary outcome will be the time-to-event progression-free survival and overall survival, and the secondary outcomes will be disease control rate, overall adverse events rate and grade 3-5 adverse events rate. Statistical heterogeneity will be assessed by visual inspection of forest plots and measured using the I statistics. A fixed-effect model will be used when heterogeneity is low otherwise, a random-effect model will be chosen. Publication bias will be assessed by funnel plots; subgroup analysis and sensitivity analysis will be performed in the right context. For each outcome, we will perform data synthesis using Rev Man V.5.3 software, and compile 'summary of findings' tables using GRADEpro software.
ETHICS AND DISSEMINATION
There is no requirement for ethics approval because no individual data will be collected in this research. It is anticipated that the dissemination of results will take place at conferences and through publication in a peer-review journal, any adjustments from the protocol will be clearly documented and explained in its final report.
PROSPERO REGISTRATION NUMBER
CRD42020177404.
Topics: Antineoplastic Agents; Hepatocyte Growth Factor; Humans; Meta-Analysis as Topic; Stomach Neoplasms; Systematic Reviews as Topic
PubMed: 34952869
DOI: 10.1136/bmjopen-2021-049575 -
Neuro-oncology Apr 2011This phase II study evaluated the efficacy and safety of AMG 102 (rilotumumab), a fully human monoclonal antibody against hepatocyte growth factor/scatter factor...
This phase II study evaluated the efficacy and safety of AMG 102 (rilotumumab), a fully human monoclonal antibody against hepatocyte growth factor/scatter factor (HGF/SF), in patients with recurrent glioblastoma (GBM). Patients with histologically confirmed, measurable recurrent GBM or gliosarcoma (World Health Organization grade 4) and ≤3 relapses or prior systemic therapies received AMG 102 (10 or 20 mg/kg) by infusion every 2 weeks. The primary endpoint was best confirmed objective response rate (central assessment) per Macdonald criteria. Of the 61 patients who enrolled, 60 received AMG 102. Twenty-nine patients (48%) had previously received bevacizumab. There were no objective responses per central assessment, but 1 patient had an objective response per investigator assessment. Median overall survival (95% CI) in the 10- and 20-mg/kg cohorts was 6.5 months (4.1-9.8) and 5.4 months (3.4-11.4), respectively, and progression-free survival (PFS) per central assessment was 4.1 weeks (4.0-4.1) and 4.3 weeks (4.1-8.1), respectively. PFS was similar among patients who had previously received bevacizumab compared with bevacizumab-naive patients. The most common adverse events were fatigue (38%), headache (33%), and peripheral edema (23%). AMG 102 serum concentrations increased approximately dose-proportionally with 2-fold accumulation at steady state. Plasma total HGF/SF and soluble c-Met concentrations increased 12.05- and 1.12-fold, respectively, from baseline during AMG 102 treatment. AMG 102 monotherapy at doses up to 20 mg/kg was not associated with significant antitumor activity in heavily pretreated patients with recurrent GBM.
Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biomarkers, Tumor; Brain Neoplasms; Female; Glioblastoma; Hepatocyte Growth Factor; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Proto-Oncogene Proteins c-met; Survival Rate; Tissue Distribution; Treatment Outcome; Young Adult
PubMed: 21297127
DOI: 10.1093/neuonc/noq198 -
NPJ Systems Biology and Applications 2019Hepatocyte growth factor (HGF) signaling through its receptor Met has been implicated in hepatocellular carcinoma tumorigenesis and progression. Met interaction with...
Hepatocyte growth factor (HGF) signaling through its receptor Met has been implicated in hepatocellular carcinoma tumorigenesis and progression. Met interaction with integrins is shown to modulate the downstream signaling to Akt and ERK (extracellular-regulated kinase). In this study, we developed a mechanistically detailed systems biology model of HGF/Met signaling pathway that incorporated specific interactions with integrins to investigate the efficacy of integrin-binding peptide, AXT050, as monotherapy and in combination with other therapeutics targeting this pathway. Here we report that the modeled dynamics of the response to AXT050 revealed that receptor trafficking is sufficient to explain the effect of Met-integrin interactions on HGF signaling. Furthermore, the model predicted patient-specific synergy and antagonism of efficacy and potency for combination of AXT050 with sorafenib, cabozantinib, and rilotumumab. Overall, the model provides a valuable framework for studying the efficacy of drugs targeting receptor tyrosine kinase interaction with integrins, and identification of synergistic drug combinations for the patients.
Topics: Anilides; Antibodies, Monoclonal, Humanized; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Computer Simulation; Drug Resistance, Neoplasm; Hep G2 Cells; Hepatocyte Growth Factor; Humans; Integrins; Liver Neoplasms; Proto-Oncogene Proteins c-met; Pyridines; Signal Transduction; Sorafenib; Systems Biology
PubMed: 31452933
DOI: 10.1038/s41540-019-0107-2 -
Cancer Aug 2017
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Erlotinib Hydrochloride; Hepatocyte Growth Factor; Humans; Lung Neoplasms
PubMed: 28472534
DOI: 10.1002/cncr.30718 -
Therapeutic Advances in Medical Oncology Nov 2011The receptor tyrosine kinase c-MET and its ligand, hepatocyte growth factor (HGF), regulate multiple cellular processes that stimulate cell proliferation, invasion and...
The receptor tyrosine kinase c-MET and its ligand, hepatocyte growth factor (HGF), regulate multiple cellular processes that stimulate cell proliferation, invasion and angiogenesis. This review provides an overview of the evidence to support c-MET or the HGF/c-MET signaling pathway as relevant targets for personalized cancer treatment based on high frequencies of c-MET and/or HGF overexpression, activation, amplification in non-small cell lung carcinoma (NSCLC), gastric, ovarian, pancreatic, thyroid, breast, head and neck, colon and kidney carcinomas. Additionally, the current knowledge of small molecule inhibitors (tivantinib [ARQ 197]), c-MET/HGF antibodies (rilotumumab and MetMAb) and mechanisms of resistance to c-MET-targeted therapies are discussed.
PubMed: 22128285
DOI: 10.1177/1758834011422557 -
Journal of Nuclear Medicine : Official... Sep 2017The hepatocyte growth factor (HGF) binding antibody rilotumumab (AMG102) was modified for use as a Zr-based immuno-PET imaging agent to noninvasively determine the local...
The hepatocyte growth factor (HGF) binding antibody rilotumumab (AMG102) was modified for use as a Zr-based immuno-PET imaging agent to noninvasively determine the local levels of HGF protein in tumors. Because recent clinical trials of HGF-targeting therapies have been largely unsuccessful in several different cancers (e.g., gastric, brain, lung), we have synthesized and validated Zr-DFO-AMG102 as a companion diagnostic for improved identification and selection of patients having high local levels of HGF in tumors. To date, patient selection has not been performed using the local levels of HGF protein in tumors. The chelator -SCN-Bn-DFO was conjugated to AMG102, radiolabeling with Zr was performed in high radiochemical yields and purity (>99%), and binding affinity of the modified antibody was confirmed using an enzyme-linked immunosorbent assay (ELISA)-type binding assay. PET imaging, biodistribution, autoradiography and immunohistochemistry, and ex vivo HGF ELISA experiments were performed on murine xenografts of U87MG (HGF-positive, MET-positive) and MKN45 (HGF-negative, MET-positive) and 4 patient-derived xenografts (MET-positive, HGF unknown). Tumor uptake of Zr-DFO-AMG102 at 120 h after injection in U87MG xenografts (HGF-positive) was high (36.8 ± 7.8 percentage injected dose per gram [%ID/g]), whereas uptake in MKN45 xenografts (HGF-negative) was 5.0 ± 1.3 %ID/g and a control of nonspecific human IgG Zr-DFO-IgG in U87MG tumors was 11.5 ± 3.3 %ID/g, demonstrating selective uptake in HGF-positive tumors. Similar experiments performed in 4 different gastric cancer patient-derived xenograft models showed low uptake of Zr-DFO-AMG102 (∼4-7 %ID/g), which corresponded with low HGF levels in these tumors (ex vivo ELISA). Autoradiography, immunohistochemical staining, and HGF ELISA assays confirmed that elevated levels of HGF protein were present only in U87MG tumors and that Zr-DFO-AMG102 uptake was closely correlated with HGF protein levels in tumors. The new immuno-PET imaging agent Zr-DFO-AMG102 was successfully synthesized, radiolabeled, and validated in vitro and in vivo to selectively accumulate in tumors with high local levels of HGF protein. These results suggest that Zr-DFO-AMG102 would be a valuable companion diagnostic tool for the noninvasive selection of patients with elevated local concentrations of HGF in tumors for planning any HGF-targeted therapy, with the potential to improve clinical outcomes.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cell Line, Tumor; Cell Transformation, Neoplastic; Deferoxamine; Female; Gene Expression Regulation, Neoplastic; Hepatocyte Growth Factor; Humans; Immunoconjugates; Mice; Patient Selection; Positron-Emission Tomography; Radioisotopes; Tissue Distribution; Zirconium
PubMed: 28280216
DOI: 10.2967/jnumed.116.187310 -
International Journal of Cancer Jun 2020Ewing sarcoma (EWS) is the second most common and aggressive type of metastatic bone tumor in adolescents and young adults. There is unmet medical need to develop and...
Ewing sarcoma (EWS) is the second most common and aggressive type of metastatic bone tumor in adolescents and young adults. There is unmet medical need to develop and test novel pharmacological targets and novel therapies to treat EWS. Here, we found that EWS expresses high levels of a p53 isoform, delta133p53. We further determined that aberrant expression of delta133p53 induced HGF secretion resulting in tumor growth and metastasis. Thereafter, we evaluated targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in preclinical studies. Surprisingly, we found that targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in combination with GD2-specific, CAR-reengineered T-cell therapy synergistically inhibited primary tumor growth and establishment of metastatic disease in preclinical models. Furthermore, our data suggested that AMG102 treatment alone might increase leukocyte infiltration including efficient CAR-T access into tumor mass and thereby improves its antitumor activity. Together, our findings warrant the development of novel CAR-T-cell therapies that incorporate HGF receptor neutralizing antibody to improve therapeutic potency, not only in EWS but also in tumors with aberrant activation of the HGF/c-MET pathway.
Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Bone Neoplasms; Cell Line, Tumor; Cell- and Tissue-Based Therapy; Hepatocyte Growth Factor; Humans; Immunotherapy, Adoptive; Mice; Proto-Oncogene Proteins c-met; Receptors, Chimeric Antigen; Sarcoma, Ewing; Signal Transduction; T-Lymphocytes; Tumor Microenvironment; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays
PubMed: 31621900
DOI: 10.1002/ijc.32743 -
British Journal of Cancer Feb 2016Pancreatic stellate cells (PSCs, which produce the stroma of pancreatic cancer (PC)) interact with cancer cells to facilitate PC growth. A candidate growth factor...
BACKGROUND
Pancreatic stellate cells (PSCs, which produce the stroma of pancreatic cancer (PC)) interact with cancer cells to facilitate PC growth. A candidate growth factor pathway that may mediate this interaction is the HGF-c-MET pathway.
METHODS
Effects of HGF inhibition (using a neutralising antibody AMG102) alone or in combination with gemcitabine were assessed (i) in vivo using an orthotopic model of PC, and (ii) in vitro using cultured PC cells (AsPC-1) and human PSCs.
RESULTS
We have shown that human PSCs (hPSCs) secrete HGF but do not express the receptor c-MET, which is present predominantly on cancer cells. HGF inhibition was as effective as standard chemotherapy in inhibiting local tumour growth but was significantly more effective than gemcitabine in reducing tumour angiogenesis and metastasis. HGF inhibition has resulted in reduced metastasis; however, interestingly this antimetastatic effect was lost when combined with gemcitabine. This suggests that gemcitabine treatment selects out a subpopulation of cancer cells with increased epithelial-mesenchymal transition (EMT) and stem-cell characteristics, as supported by our findings of increased expression of EMT and stem-cell markers in tumour sections from our animal model. In vitro studies showed that hPSC secretions induced proliferation and migration, but inhibited apoptosis, of cancer cells. These effects were countered by pretreatment of hPSC secretions with a HGF-neutralising antibody but not by gemcitabine, indicating a key role for HGF in PSC-PC interactions.
CONCLUSIONS
Our studies suggest that targeted therapy to inhibit stromal-tumour interactions mediated by the HGF-c-MET pathway may represent a novel therapeutic approach in PC that will require careful modelling for optimal integration with existing treatment modalities.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Cell Proliferation; Deoxycytidine; Epithelial-Mesenchymal Transition; Hepatocyte Growth Factor; Humans; In Vitro Techniques; Mice; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Pancreatic Neoplasms; Pancreatic Stellate Cells; Proto-Oncogene Proteins c-met; Xenograft Model Antitumor Assays; Gemcitabine
PubMed: 26766740
DOI: 10.1038/bjc.2015.478 -
Neoplasia (New York, N.Y.) May 2009A common mutation of the epidermal growth factor receptor (EGFR) in glioblastoma multiforme (GBM) is an extracellular truncation known as the de2-7 EGFR (or EGFRvIII)....
A common mutation of the epidermal growth factor receptor (EGFR) in glioblastoma multiforme (GBM) is an extracellular truncation known as the de2-7 EGFR (or EGFRvIII). Hepatocyte growth factor (HGF) is the ligand for the receptor tyrosine kinase (RTK) c-Met, and this signaling axis is often active in GBM. The expression of the HGF/c-Met axis or de2-7 EGFR independently enhances GBM growth and invasiveness, particularly through the phosphatidylinositol-3 kinase/pAkt pathway. Using RTK arrays, we show that expression of de2-7 EGFR in U87MG GBM cells leads to the coactivation of several RTKs, including platelet-derived growth factor receptor beta and c-Met. A neutralizing antibody to HGF (AMG102) did not inhibit de2-7 EGFR-mediated activation of c-Met, demonstrating that it is ligand-independent. Therapy for parental U87MG xenografts with AMG 102 resulted in significant inhibition of tumor growth, whereas U87MG.Delta 2-7 xenografts were profoundly resistant. Treatment of U87MG.Delta 2-7 xenografts with panitumumab, an anti-EGFR antibody, only partially inhibited tumor growth as xenografts rapidly reverted to the HGF/c-Met signaling pathway. Cotreatment with panitumumab and AMG 102 prevented this escape leading to significant tumor inhibition through an apoptotic mechanism, consistent with the induction of oncogenic shock. This observation provides a rationale for using panitumumab and AMG 102 in combination for the treatment of GBM patients. These results illustrate that GBM cells can rapidly change the RTK driving their oncogene addiction if the alternate RTK signals through the same downstream pathway. Consequently, inhibition of a dominant oncogene by targeted therapy can alter the hierarchy of RTKs resulting in rapid therapeutic resistance.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Blotting, Western; Brain Neoplasms; Cell Line, Tumor; Drug Delivery Systems; Enzyme Activation; ErbB Receptors; Glioblastoma; Hepatocyte Growth Factor; Humans; Immunohistochemistry; Mice; Oncogenes; Panitumumab; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-met; Receptor Protein-Tyrosine Kinases; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 19412429
DOI: 10.1593/neo.09230 -
Journal of Cellular and Molecular... Sep 2011The hepatocyte growth factor (HGF)/Met signalling pathway is up-regulated in many cancers, with downstream mediators playing a role in DNA double strand break repair....
The hepatocyte growth factor (HGF)/Met signalling pathway is up-regulated in many cancers, with downstream mediators playing a role in DNA double strand break repair. Previous studies have shown increased radiosensitization of tumours through modulation of Met signalling by genetic methods. We investigated the effects of the anti-HGF monoclonal antibody, AMG102, on the response to ionizing radiation in a model of glioblastoma multiforme in vitro and in vivo. Radiosensitivity was evaluated in vitro in the U-87 MG human glioma cell line. Met activation was measured by Western blot, and the effect on survival following radiation was evaluated by clonogenic assay. Mechanism of cell death was evaluated by apoptosis and mitotic catastrophe assays. DNA damage was quantitated by γH2AX foci and neutral comet assay. Growth kinetics of subcutaneous tumours was used to assess the effects of AMG102 on in vivo tumour radiosensitivity. AMG102 inhibited Met activation after irradiation. An enhancement of radiation cell killing was shown with no toxicity using drug alone. Retention of γH2AX foci at 6 and 24 hrs following the drug/radiation combination indicated an inhibition of DNA repair following radiation, and comet assay confirmed DNA damage persisting over the same duration. At 48 and 72 hrs following radiation, a significant increase of cells undergoing mitotic catastrophe was seen in the drug/radiation treated cells. Growth of subcutaneous tumours was slowed in combination treated mice, with an effect that was greater than additive for each modality individually. Modulation of Met signalling with AMG102 may prove a novel radiation sensitizing strategy. Our data indicate that DNA repair processes downstream of Met are impaired leading to increased cell death through mitotic catastrophe.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing; Cell Death; Cell Line, Tumor; Cell Proliferation; DNA Damage; Glioma; Hepatocyte Growth Factor; Humans; Mice; Mice, Nude; Proto-Oncogene Proteins c-met; Radiation Tolerance; Radiation, Ionizing; Signal Transduction
PubMed: 20629992
DOI: 10.1111/j.1582-4934.2010.01122.x